Systems and methods for broad line fundus imaging

ABSTRACT

Systems and methods for Broad Line Fundus Imaging (BLFI), an imaging approach that is a hybrid between confocal and widefield imaging systems, are presented. These systems and methods are focused on improving the quality and signal of broad line fundus images or imaging methods to create high contrast and high resolution fundus images. Embodiments related to improved pupil splitting, artifact removal, reflex minimization, adaptable field of view, instrument alignment and illumination details are considered.

PRIORITY

The present application is a divisional of U.S. application Ser. No.14/207,229, filed Mar. 12, 2014, which claims priority to U.S.Provisional Application Ser. No. 61/799,257, filed Mar. 15, 2013, thecontents of each of which are hereby incorporated in their entirety byreference.

TECHNICAL FIELD

This application is related to the field of fundus imaging, inparticular improved systems and methods for broad line fundus imaging.

BACKGROUND

A variety of imaging modalities have been applied to generating imagesof the retina or fundus of the eye. Two well established techniques arewidefield imaging typically accomplished by classic fundus cameras andconfocal scanning laser ophthalmoscope (cSLO) imaging designs. Funduscameras illuminate large fields of the retina typically with a flashlamp and take still photos with a two-dimensional camera. To avoiddetecting specular reflections of the illumination light at the cornea,a ring-shaped mirror reflects the illumination light to the eye creatingan annular aperture near the cornea, which does not overlap with thecentral disc like aperture which is used for detection. Thus aseparation of the illumination and detection path near the cornea isrealized, which is known as aperture or pupil splitting. To preventspecular reflections of the illumination light at optical surfaces ofthe fundus camera itself, especially from the ophthalmic lens, frombeing detected by the camera, so called dark spots in the illuminationpath prevent that specific surface area of the optics from beingilluminated. Fundus cameras have the advantage that taking images of theretina is fast, thus for example no movement artifacts are observed, andthey realize a high lateral resolution with high signal level anddynamic range.

Widefield imaging systems such as fundus cameras have the followinglimitations:

-   -   1. They collect light from all depths within the eye, leading to        issues with contrast and reflexes. Thus the contrast in fundus        images can be low, which is especially observed in eyes having        cataracts.    -   2. The need to eliminate reflexes puts strict constraints on the        system, limiting the field of view to roughly 60 degrees, and        making it difficult to combine with other modalities.    -   3. Finally, the full field of view of the imaging system is used        simultaneously, eliminating the option of dynamic adaptive        optics for image enhancement.

Another concept of imaging the retina is realized by point confocalscanning systems. These systems image the fundus by illuminating a smallspot of the retina with a laser and detecting the reflected or emittedlight (e.g. in case for fluorescence modes) by a detector with a pinholein front of the detector. This pinhole is optically conjugated to theilluminated spot on the retina. Due to the confocal arrangement ofillumination and detection, stray-light and out of focus light issuppressed. For imaging the retina the spot is laterally scanned.Confocal scanners have the advantage of suppressing out of focus light,thus showing high contrast images.

Point scanning confocal imaging systems such as a cSLO have thefollowing limitations:

-   -   1. They operate with point illumination, requiring the use of        lasers or SLDs, which are expensive, and creating a high        instantaneous intensity on the eye, making safety more        challenging.    -   2. As each point is imaged sequentially, they require fast        transverse scanning to avoid motion artifacts, which is        expensive, and may require resonant scanners, which limit        imaging flexibility.    -   3. It can be difficult to achieve enough confocality to        completely eliminate the eye reflex, and such a confocal system        causes structures such as the optic disk to appear dark because        they are not in the plane of the retina.

Another concept for imaging the retina is realized in line scanningsystems. In contrast to point confocal systems a line instead of a pointis illuminated by a laser and detected at a camera. These systemsmaintain confocal suppression of out of focus light perpendicular to theline but lack the confocal suppression along the line. The line width indetection can be adapted to the amount of suppression of out of focuslight that is necessary. Line scanning has been combined with aperturesplitting known from classical fundus imaging (see for example Muller etal. US Patent Publication No. 2010/0128221) and also with ellipsiodalmodifications of the illumination pupil to avoid vignetting and to get auniformly illuminated line at the retina. Muller et al. also disclosesso called non-de-scanned or imaged systems, where the scanning over theretina is realized only in illuminating or scanning line illuminationover the retina and scanning line detection over the retina is realizedby different mechanisms.

The advantage of the line scanning system according to Muller is that itcan scan faster across the retina, thus being less sensitive to motionartifacts, but at the expense of less out of focus suppression. Butstill motion artifacts are observed and lateral resolution and dynamicrange is limited compared to fundus cameras. In addition often contrastis also limited because stray-light even coming from areas perpendicularto the line is still present in the detected signal.

Line scanning also creates new problems:

-   -   1. Variations in line intensity or linear array sensitivity lead        to streaking in the image.    -   2. Confocality is reduced, requiring a mask to eliminate the eye        reflex. This mask compromises the optical efficiency of the        system, leading to dim images.

Another concept of imaging the retina is the broad line scanner andmethod described in WO2012059236 by Bublitz. Bublitz discloses basicelements of a broad line fundus imager (BLFI) and methods. Bublitzfurther discloses the usage of LED sources with higher etendues thanlasers, which is possible in contrast to a classical line scannerbecause the field of a broad line illumination is significantly widerthan the line of a confocal line scanner. Bublitz further discloses thatcamera locations whose corresponding locations on the retina are notilluminated can be detected to evaluate background or stray light levelscoming from out of focus region of the eye. This background is thensubtracted from the image of the illuminated broad line. Bublitz alsodiscloses a different pupil splitting for illumination and detectionnear the cornea than is typical for fundus cameras: instead ofillumination of an annular ring, a slit is illuminated, and thedetection is done via two caps of a disc at the periphery of theaperture. In addition, the orientation of the illumination slit isperpendicular to the illumination line at the retina.

Bublitz discloses a non-de-scanned detection setup using an electronicor rolling shutter camera with activated camera lines, when thecorresponding line of the fundus is illuminated by the broad line orwhen background level is measured, but as described by German PatentApplication No. DE 10 2011 053 880.1 also a de-scanned detection schemeallowing for continuous scanning can be used.

The advantage of the designs disclosed by Bublitz is that for each ofthe line images the benefits of classical fundus cameras are achieved:long integration times due to broad line illumination, high dynamicrange, high lateral resolution due to broad line image being 2D-sampledby a high resolution 2D-camera, usage of classical light sources or LEDshaving a broader wavelength spectra than lasers. Also due to fasterscans, motion artifacts are reduced. In addition, a significantreduction in sensitivity to stray light by not illuminating the wholeretina and measurement of background/stray light level and subtractioncan be achieved. Thus the images show better contrast. But experimentshave shown that further improvements are necessary to get resultcomparable to confocal scanners. In addition, motion artifacts stilloccur, due to each line of the camera having its unique illuminationtime window, when the data for that specific camera line is detected.

SUMMARY

Here, we propose improved systems and methods for Broad Line FundusImaging (BLFI), an imaging approach that is a hybrid between confocaland widefield systems. These hybrid designs have the potential to createhigh contrast fundus images using low cost light sources (LEDs) withresolution similar to a classic fundus camera. The term broad is usedherein to distinguish from classic line scanning systems where the beamis focused to a line limited by diffraction and optical aberrations andthe source is typically a laser or a superluminescent diode (SLD).

The broad line fundus imaging (BLFI) scanning system design comprisesthe following elements:

-   -   1. Stepping or scanning of a small region of illumination across        the eye so as to generate an image of the full area of interest.        A first aperture, confocal to this illumination, collects the        light from the retina to generate a “bright image”. This        aperture limits stray and reflex light from other planes to a        manageable level, but need not be small enough to eliminate it.    -   2. Optional acquisition and subtraction of a “dark image” to        remove the unwanted stray and scattered light so as to generate        a high contrast reflex free image.    -   3. If scattering and reflexes from the eye are an issue, this        dark image can be acquired through a second aperture, slightly        misaligned to the illumination, that collects the limited stray        and reflex light, but does not collect image light. Depending on        the design, acquisition through this second aperture can be        either simultaneous with or sequential to collection through the        first aperture. Note that it may be important to acquire dark        images for color imaging in the presence of a cataract, where        there will be additional out of focus scattering.    -   4. Further, to reduce or eliminate reflexes from the lenses of        the acquisition system, a “no-eye” image without the object can        be acquired prior to the image acquisition, potentially during        manufacture of the instrument.

The key advantages of such a hybrid system are as follows:

-   -   1. As multiple pixels are acquired simultaneously, a high        (compared to a laser) etendue light source such as an LED can be        used, and high pixel count images can be generated.    -   2. This makes a low cost imaging system possible, with the high        pixel count of a classic fundus camera, but greatly improved        contrast.    -   3. The relatively large aperture used in this approach improves        sensitivity to slightly out of focus light. This could improve        imaging of the optic disk and retinal features such as drusen        that are displaced axially from the retinal pigment epithelium        (RPE), and improve the ability to image a large field of view in        the presence of myopia.

This BLFI imaging system can have several variants:

-   -   1. Separation of illumination and detection can be achieved        either using a dielectric mirror or via a pupil splitting mirror        to selectively separate components of the light reflected from        the eye and the illumination. Typically, a dielectric mirror        would be used for fluorescence imaging and pupil splitting for        color imaging    -   2. Bright and dark images can be acquired either sequentially or        simultaneously. The imaging can be using either de-scanned or        non-de-scanned (imaged) detection. The distinction being in a        de-scanned system, the same region of interest is used for        different locations in the retina while in non-de-scanned or        imaged detection there is a one to one correspondence between        points on the retina and points on the detector array.    -   3. If a particular wavelength is required that is not available        with LEDs, a laser could be substituted for the LEDs, but at the        risk of increased speckle in the images.

It is clearly better to acquire both the bright and dark imagessimultaneously as otherwise any motion of the eye between acquisitionswill lead to artifacts in the final image due to incorrect subtractionof the background Likewise, interlaced color imaging is preferred oversequential imaging of the full image in each color as motion duringsequential imaging can lead to misalignment between colors in the finalimage.

De-scanning detection of the scanned beam simplifies the acquisition asthe same detector elements are used repeatedly for each bright and darkframe. However, as the individual elements in the detector array arescanned across the retina, there cannot be motion of the scanner duringany individual acquisition. This requires that the scanner steps betweenacquisitions and stops during the acquisition. A second issue is thatlight collected from the center of the aperture is likely more intensethan the light collected from the edges of the aperture, leading to aspatial modulation in image brightness with a spatial periodcorresponding to the detector aperture size. For a homogeneousLED-illumination that problem is likely solvable either by illuminatingan area of the retina that is slightly larger than the area that can beimaged through the collection aperture, or by overlapping the acquiredregions during the reconstruction of the image to prevent slit edgeeffects.

It is an object of the present invention to improve image quality andsignal of broad line fundus images or imaging methods. In oneembodiment, this is achieved by further minimizing the overlap betweenillumination and detection paths and eliminating or reducing reflexesusing different pupil splitting arrangements than what has been used inthe prior art. In a second embodiment, an improvement is realized byminimizing or enabling easy removal of motion artifacts and backgroundsuch as stray light signal using a step-scan illumination/detectionapproach. In another embodiment, image improvement is realized bydesigns directed towards minimizing reflexes in the system. This can beachieved dynamically during image acquisition by adjusting systemparameters such as the tilt of the ophthalmic lens, or the illuminationor collection widths.

It is a further object of the invention to disclose solutions todifferent challenges in BLFI imaging. In one embodiment, it is possibleto adapt the field of view of the instrument by adding or replacing anoptical component with optional changing of the pupil splittingconfiguration. In another embodiment, specific details of light sourcesfor use in BLFI imaging are described. In another embodiment techniquesfor aligning the instrument are presented.

The various embodiments of the present invention can be applied to oneor more variants of BLFI imaging systems which will be described indetail. Aspects of some of the variants are also considered inventive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates four different broad line fundus imaging systemvariants. FIG. 1a illustrates the basic components of a de-scannedsystem. FIG. 1b illustrated a scanned or imaged detection configuration.FIG. 1c illustrates an imaged or scanned detection arrangement but isrealized without an actual scanner. FIG. 1d shows a fourth variant inwhich both the front and back surfaces of the scanner are used inimaging.

FIG. 2 illustrates combining of multiple LEDS into a single virtual LEDsource for use in broad line fundus imaging systems. FIG. 2a shows theside view while FIG. 2b shows the front view looking into the LED chip.FIG. 2c illustrates an additional LED combining scheme for 3 LEDs.

FIG. 3 illustrates two different light conditioning scenarios to makedifferent light sources more suitable for use in broad line fundusimaging systems. FIG. 3a shows the combining of multiple color LEDs andFIG. 3b shows the conditioning that could be applied to a laser sourceto make it suitable for broad line fundus imaging,

FIG. 4 illustrates a multimodality system combining a broad line fundusimaging system with an optical coherence tomography (OCT) system.

FIG. 5 illustrates one strip or stripe image from a broad line fundusimaging system.

FIG. 6 illustrates the imaging relationship between the illuminationaperture and the pupil plane for reduced vignetting.

FIG. 7 illustrates depth discrimination functions corresponding to thepart of light reflected in a plane at a certain distance to the focus(x-axis) that could be detected behind the confocal aperture stop for aplurality of optical imaging systems.

FIG. 8 illustrates various pupil splitting arrangements. FIGS. 8a, 8b,8c, 8d and 8f illustrate a plurality of pupil splitting scenarios forfundus imaging systems as viewed at the pupil aperture. FIG. 8e is apreferred pupil splitting scheme for broad line fundus imaging systems.

FIG. 9 illustrates relationships between pupil splitting and retinaillumination directions for small and large pupil conditions in aparticular pupil splitting arrangement.

FIG. 10 illustrates the relationships between width of no-man's land,the illumination width and the eye length.

FIG. 11 illustrates a broad line fundus imaging system.

FIG. 12 illustrates the relationships between width of no-man's land,the illumination width and the eye length for an optical surface imagedbehind the retina.

FIG. 13a illustrates a case where the pupil splitting betweenillumination and collection paths is complete in the dimensionperpendicular to the pupil splitting looking along the line ofillumination on the retina. The pupil splitting along the line ofillumination leads to significant overlap as shown in FIG. 13 b.

FIG. 14 illustrates possible pupil splitting schemes for small and largepupils.

FIG. 15 illustrates a broad line fundus imaging system with a fixedcollection aperture.

DETAILED DESCRIPTION

BLFI Variants

Several variants of the broad line fundus imaging (BLFI) system arepossible as illustrated in FIG. 1. FIG. 1a illustrates the basiccomponents of a de-scanned system as is currently the preferredembodiment for a BLFI system. One or more light sources 101, preferablya multi-color LED system or a laser system in which the etendue has beensuitably adjusted. In a preferred embodiment, light from red, green,blue, and IR LEDs are collimated and coupled together by dichroicmirrors and then focused in an optical microlens array or rod/taper. Ina preferred embodiment using the microlens array, the LEDs areindividually collimated and then the collimated LEDs are combined with asingle lens to create a source with uniform illumination spatially andin the angular direction as is described in further detail below (FIG.2). The IR light is typically used to generate an alignment image thatcan be displayed in real time to the user. The emission of the BLFIlight source in the configuration shown in FIG 1a is much narrower inone direction than the other since when there is no unique (orfull-field) mapping between the emission area of the light source andthe retina, the emission area of the light source only needs to have theaspect ratio of the solid angle of detection that the illuminated regionon the retina has and does not need to have the aspect ratio of theentire imaged area of the retina. An adjustable slit 102 is positionedin front of the light source to determine the illumination line width.This could also be established by the source independent of a slit oraperture. In the embodiment shown on FIG. 1 a, this slit remains staticduring the imaging but can be adjusted to different widths to allow fordifferent confocality levels and different applications either for aparticular scan or during the scan for use in suppressing reflexes asdescribed in further detail below. An objective lens 103 forms a pupilof the slit. The objective lens can be any one of state of the artlenses including but not limited to refractive, diffractive, reflective,or hybrid lenses/systems. The light passes through a pupil splittingmirror 104 and is directed towards a scanner 105. It is desirable tobring the scanning plane and the pupil plane as near together aspossible to reduce vignetting in the system as will be discussed infurther detail below. Optional optics 108 may be included to manipulatethe optical distance between the images of the two components. The maintask of the pupil splitter is to combine and split the illumination anddetection beams and to aid in the suppression of system reflexes. Asdescribed in further detail below, specific pupil splittingconfigurations are desired for different applications and optimizedscanning. The scanner 105 could be a rotating galvo scanner or othertypes of scanners (i.e. piezo or voice coil). Depending on whether thepupil splitting is done before or after the scanner, the scanning couldbe broken into two steps wherein one scanner is in the illumination pathand a separate scanner is in the detection path.

From the scanner, the light passes through one or more optics, in thiscase a scanning lens (SL) 106 and an ophthalmic or ocular lens (OL) 107,that allow for the pupil of the eye 109 to be imaged to an image pupilof the system. One possible configuration for these optics is a Kepplertype telescope wherein the distance between the two lenses is selectedto create an approximately telecentric intermediate fundus image (4-fconfiguration). The ophthalmic lens could be a single lens, anachromatic lens or an arrangement of different lenses. All lenses couldbe refractive, diffractive, reflective or hybrid as known to one skilledin the art. The focal length(s) of the ophthalmic lens, scan lens andthe size and/or form of the pupil splitting and scanning mirrors couldbe different depending on the desired field of view (FOV), and so anarrangement in which multiple components can be switched in and out ofthe beam path, for example by using a flip in optic, a motorized wheel,or a detachable optical element, depending on the field of view can beenvisioned. Since the field of view change results in a different beamsize on the pupil, the pupil splitting can also be changed inconjunction with the change to the FOV. It is possible to have a 45°-60°field of view as is typical for fundus cameras. Higher fields of view(60°-120°) may be desired for a combination of the BLFI with otherimaging modalities such as optical coherence tomography (OCT) as will bediscussed in further detail below. The upper limit for the field of viewwill be determined by the accessible working distance in combinationwith the physiological conditions around the human eye. Because atypical human retina has a FOV of 140° horizontal and 80°-100° vertical,it may be desirable to have an asymmetrical field of view for thehighest possible FOV on the system.

The light passes through the pupil of the eye and is directed towardsthe retinal surface. The scanner adjusts the location of the light onthe retina or fundus such that a range of transverse locations on theeye are illuminated. Reflected or scattered light (or emitted light inthe case of fluorescence imaging) is directed back along the same pathas the illumination. While reflected light is typically used in thepresent document to describe the light returning from the eye, it isintended for reflected to include scattered light and it should berecognized that the words reflected and emitted could be usedinterchangeably depending on the desired imaging modality.

At the pupil splitting mirror, the reflected light is separated from theillumination light and directed towards a camera 110. In a preferredembodiment the splitting between the illumination and the detection isachieved in a specific direction as described in further detail below.In particular, it is desirable that the etendue of the illumination beamis lower in that direction than in the orthogonal direction. Thesplitting can be designed such that the extent of illumination in thepupil can be narrower in the lower etendue direction and/or the angulardistribution of the illumination light can be lower in the direction ofthe splitting as compared to the orthogonal direction. An objective lens111 exists in the detection path to image the fundus to the camera. Asis the case for objective lens 103, objective lens 111 could be any typeof refractive, diffractive, reflective or hybrid lens as is known by oneskilled in the art. Only a strip like region of the fundus will beilluminated and detected at once. Due to this, one part of the reflexand scattering interfering light from other optics in the system or theeye will be suppressed. The strongest reflex in the system is thecorneal reflex. Optimized suppression of this reflex can be achieved ina number of ways as described in detail below. In a preferredembodiment, the illumination and detection zones are parallel to thearea illuminated on the retina and separated by a “no-man's” zone aswill be described in further detail below.

In the embodiment shown in FIG. 1 a, the detection scheme is describedas “de-scanned”, in which the illumination light and light reflected bythe fundus will both be deflected by the scanner (or the illuminationand reflected light are deflected by two different scanners one timeeach as previously described). In this arrangement, the illuminationslit and the detector are aligned fixed to each other and the funduswill be effectively “scanned” over the pixels of the camera. The cameracan be operated in a global shutter configuration in which all pixels ordetector elements are active during the acquisition. Descanning of thescanned beam simplifies the acquisition as the same detector elements orregions of interest (ROIs) are used repeatedly for each bright and darkframe. However, as the individual elements in the detector array arescanned across the retina, there cannot be motion of the scanner duringany individual acquisition. To avoid the effects of motion, a timedelayed integration (TDI) camera as described in German PatentApplication No. DE 10 2011 053 880.1 hereby incorporated by referencecan be used. In such a camera the acquired charges will be transferredto the next line of pixels when the light being scanned on the fundushas moved one pixel line as well. An alternative and preferred approachto the use of a TDI camera is to use a normal two dimensional spatialresolved camera and stop the scanner during the image integration ineach broad line zone or strip. The scanner steps between acquisitionsand stops during the acquisition as is discussed in further detailbelow.

In a second variant of the BLFI technology that is illustrated in FIG. 1b, the detection is realized in a scanned or imaged configuration, suchthat during the time of acquisition, an entire image of the retina isbuilt up on the camera with each position on the retina being uniquelymapped to a position on the camera and vice versa. In this type ofconfiguration, only the illumination light is scanned and the lightreflected (or emitted) from the eye is split at the pupil splittingmirror 204 in front of the scanner 205 and directed towards a twodimensional position sensitive detector (camera 210). A moving slit oraperture is positioned in front of the camera and is moved synchronouslywith the scanner. In an alternative approach, the slit could be staticand the slit and camera could be moved together to realize the sameeffect. Alternatively some sort of electronic aperturing or shutteringof the camera could be employed as is well known in the prior art (seefor example Humphrey et al. U.S. Pat. No. 4,732,466 and Webb U.S. Pat.No. 5,028,802 hereby incorporated by reference). The lenses shown inFIG. 1b are of the same types and provide the same functions as thelenses in FIG. 1 a. A “double rolling shutter” functionality isdescribed in PCT Publication No. WO 2012/059236. In this configuration,at least two ROIs for the bright and dark images are designated andmoved synchronously to the scanning of the illumination. This approachallows for optimized light efficiency and image quality.

A third variant of the BLFI technology is illustrated in FIG. 1 c. Thisconfiguration corresponds to an imaged or scanned detection arrangementbut is realized without an actual scanner. Instead, a moving slit 312 infront of the camera 310 is moved synchronously with a moving slit 313 infront of the light source 301. Instead of a moving slit in front of thecamera, a slit that is static with respect to the camera could be usedand the camera and static slit could be moved together relative to therest of the optical system. In this case, the emission area of the lightsource has the same aspect ratio as the image that is acquired.Similarly, instead of a moving slit in front of the light source, a slitthat is static with respect to the source could be used and the lightsource and slit could be moved together relative to the rest of theoptical system. In this case, the emission area of the light source canbe narrower in one direction than in the other similar to the embodimentillustrated in FIG. 1 a. Similar to the BLFI variant illustrated in FIG.1 b, each position in the retina is uniquely mapped to a position on thecamera and vice versa. In addition, if the light source is static andthe slit in front of it is moving, each position on the emission area ofthe light source is uniquely mapped to a position on the camera and viceversa. The width of the light source could also be a property of thesource not requiring a slit.

FIG. 1d shows a fourth variant of BLFI technology in which the frontsurface of the scanner 405 scans the illumination light and thereflected light and the back surface of the scanner is used to scan thereflected light over the camera 410. Mirror 414 is used as the apertureequivalent to the moving slit in front of the camera in FIGS. 1b and 1c. A single lens 413 can be used to focus the beam onto mirror 414 andredirect the light reflected from the mirror to the camera. The point atwhich light passes through lens 413 after reflection on mirror 414 is ata different location than where it passes through the lens on the way tomirror 414. In other words, the entry point on lens 413 is off axisrelative to the center of the lens. The emission area of the lightsource is much thinner in one direction than the other. Each position ofthe retina is uniquely mapped to a position on the camera and viceversa.

In all variants of the technology illustrated in FIG. 1, the camera canbe connected to a processor and/or a display. The processing anddisplaying modules can be included with the instrument itself or on adedicated processing and displaying unit, such as a personal computer,wherein data is passed from the camera to the processor over a cable ornetwork including wireless networks. The display can include a userinterface for displaying information to and receiving information froman instrument operator or user. For de-scanned systems in which theimage is built up in parts, the processor is responsible for combiningor mosaicking the multiplicity of images collected while stepping thescanner and combining them into a single image. In the processor,various steps are employed to generate the highest quality image as willbe described in further detail below. In addition to the images of thearea of interest, it is possible to collect dark images that can besubtracted to reduce or eliminate the effects of stray light or reflexesfrom optical surfaces in the instrument or other locations in the eyethat may appear in the image. One aspect of the present inventionincludes improved techniques for background subtraction as will bedescribed in further detail below.

Light Source Considerations

As previously mentioned, a multi-color LED illumination could be usedfor BLFI imaging. For example as illustrated in FIG. 3a , a blue, agreen, a red and an infrared LED could be collimated with condenserlenses, coupled together with dichroic beam splitters and then focusedwith a lens into a mixing rod/taper/microlens array or other types oflight homogenization device.

To realize a strip like illumination pattern in the exit plane of thehomogenization device, a slit like aperture stop can be used. It ispossible to establish motorized control of the slit width to adapt theBLFI to different confocality levels/applications. The homogenizationdevice could additionally work as an etendue preserving toric fieldconverter to adapt the light distribution efficiently in front of theaperture stop. A third function of the mixing device could be to adaptthe telecentricity of the illumination light to that one of thefollowing main objective lens.

To suppress the cornea reflex near a pupil plane, it could help tohomogenize the light in the field and in the angular (far field)distribution. Therefore multilevel homogenization setups could be used.For example it would be possible to collimate the LEDs with compoundparabolic concentrators or similar devices that work beside thecollimation as a first level homogenization device. This basic setup isfor acquiring color, FA and FAF images. To acquire ICG images or veryhigh quality FA and FAF images, a laser source could be coupled in.Therefore in the front of the slit like aperture stop, a certain freedistance could be intended with a motorized mirror to couple in anyadditional kind of light source that could be modularly exchanged. Thisis called a universal illumination port.

Because only a broad line in the fundus should be illuminated, an LEDchip is needed which should be much longer than wide. Because onlysymmetric square chips are available, it is possible to use larger ones.Multichip LEDs that are elongated rectangular are one approach, or morepreferred one could use square or rectangular chips over theirdiagonals.

For some wavelengths, for example 770 nm, which is necessary for ICGexcitation, no high power large chip LEDs are available. For the typicaletendue of a BLFI imaging system, at least 3 mm×1 mm LED chip size isnecessary. Because only 1 mm LED chips are available for that color itis possible to realize a compound LED source with the etendue of a 3×1mm chips.

A possible arrangement for a source consisting of seven LED chips isshown in FIG. 2a . Twelve chip and even higher numbers are possible withthe same approach. FIG. 2a shows a sectional view, FIG. 2b shows the topview of the same arrangement in FIG. 2a . For the etendue required forBLFI, a special version of this source could be used with only 3 LED+collimators arranged in a line as shown in FIG. 2(c). Each lightemitting element (preferably LED) is separately collimated. Thecollimated beams are combined with a single lens. The resulting lightbeam has relatively uniform angular and spatial distributions.

It is further preferred to use laser as illumination source for specialwavelength or special applications like ICG-angiography. But in contrastto state of the art LSLO (laser scanning line ophthalmoscopes), thelaser light has to be converted by a non-etendue preserving element. Theetendue of the laser should be enlarged from a diffraction limited beamto the etendue that could be transmitted of the BLFI. It is veryimportant that the etendue of the so formed laser will fit quite well tothe one of the setup, because larger etendues reduce the lightefficiency of the setup and smaller etendues would enhance theexposure/hazard level in ophthalmoscopic applications.

For the iris plane, the laser forms a very narrow line distribution too.Because this line will be stationary during the scanning it could beharmful to the iris tissue. For that reason it is necessary to enlargethe illumination line in the pupil plane from a few microns to at least0.1-2 mm or more determined by the exact shape of the illumination zonesshown in FIG. 8. For that purpose a scattering disc can be located inthe illumination source directly in front of the slit like aperture stopto enlarge the etendue to safe levels (see FIG. 3b )). The scatteringdisc could have a motorized control distance to the aperture stop plane.While preserving the line width of the intensity distribution in theiris plane, you can control/adapt the line width in the retina plane andwith it the confocality level with that distance.

Because of safety reasons it is mandatory to use scattering discs thathave minimized hotspots in the near-, the far- and all intermediatefields. Due to this, only statistical microlens arrays or statisticalscattering discs are preferred. Additionally it is preferred to usescattering devices that form a top-hat like far field distribution tohomogeneous illuminate the retina in BLFI imaging.

In applications where speckle is a problem, the scattering disc can berotated at a high speeds to average the speckle structures in the retinaplane (and the harmful hotspots in all other planes). Because of theposition of the scattering disc in front of the slit like aperture stop,the disc can control both the slit width in the iris for safety reasonsand the width of the retina slit for adapting the confocality level todifferent application.

Multimodality Considerations

FIG. 4 shows the combination of the BLFI variant illustrated in FIG. 1awith an optical coherence tomography (OCT) system 501. One such systemis described in detail in US Patent Publication No. 2007/0291277 herebyincorporated by reference. Any variant of OCT (time domain (TD),spectral domain (SD), swept-source (SS), full field (FF), orinterferometric synthertic aperture microscopy (ISAM) could be combinedwith BLFI. The only addition to the BLFI beampath required is abeamsplitter BS1 502 used to reflect the OCT light and transmit the BLFIlight. OCT systems typically operate in the infrared (800-1300 nm), so afilter capable of transmitting visible and reflected near IR would bedesirable. In the configuration illustrated in FIG. 4, the OCT isintroduced between the scanner and the eye between the scanning andophthalmic lenses. The OCT system could be introduced on the other sideof the scan lens and even on the other side of the scanner and the samescanner could be used for both imaging modalities. The BLFI system couldbe used to provide images for tracking as described in US PatentPublication No. 2006/0228011 and US Patent Publication No. 2012/0249956hereby incorporated by reference. While OCT is shown here, BLFI can ingeneral, be combined with other optical metrology systems to provideadditional data or aid the operator in using the system optimally,potentially aiding in alignment, exposure time setting, fixation, etc.

Alignment and Focusing Considerations

Achieving optimal focusing of a de-scanned BLFI instrument can beaccomplished using a live stream of IR images generating by onlyilluminating the eye with light from an IR LED. FIG. 5 shows an imagegenerated from a de-scanned BLFI configuration as illustrated in FIG. 1a. Here, it is possible to view a bright area 1001 in the center of theimage. This corresponds to the location of the illumination beam on theretina at that particular scanning step. The sharpness of the edge ofthe illumination area can be used to find the optimized focus of thesystem. This could be accomplished automatically by the instrument.Because the numerical aperture in the detection is much less that in theillumination, the illumination sharpness is much more depth dependentthan the detection sharpness and so a very sensitive image sharpnessparameter is created. If the illuminated area is near the fundus center,it is also possible to evaluate the focus position/edge sharpness alongthe illumination area and therefore the sharpness would depend on thefield of view (FOV). In this case the optimal focus position for thewhole FOV could be found. This is very important for large FOVsespecially in the case of highly myopic eyes.

A method for aligning the instrument and thus especially aligning thepupil splitting near the cornea could be realized for all detectionconfigurations (de-scanned, non-de-scanned, hybrid), by using anadditional camera for capturing images of the pupil and iris of thepatient. Such a camera, commonly referred to as an iris camera, has beenrealized in optical coherence tomography systems as described in USPatent Publication No. 2007/0291277 hereby incorporated by reference.For BLFI, an iris camera could be introduced between the scanning lens(SL) and the scanning plane in any one of the BLFI variants illustratedin FIG. 1. The system could find the optimal distance between theinstrument and the eye by identifying an iris camera image with minimalvignetting. Alternatively, the overall sharpness of the image could beevaluated as the optimal separation between the instrument and the eyewill result in the sharpest image. Both qualities could be evaluatedautomatically by the instrument using software algorithms in theprocessor. Alternatively, images could be provided to the user tomanually focus the instrument.

Vignetting Considerations

Vignetting or reduction in brightness or saturation at the peripherycompared to the image center in BLFI images can be minimized usingseveral design considerations relating to the illumination anddetection. For the illumination path, it is important that the effectivepivot point of scanning is imaged to the pupil of the eye. If theillumination pupil aperture has structure in the non-scanned direction,this must be imaged to the pupil. It is not critical for structure inthe illumination pupil aperture in the scanned direction to be imaged topupil assuming the etendue of the light is highly limited in the scandirection. In addition, the far field illumination of the retinaaperture must be at the pupil plane as illustrated in FIG. 6.

With regards to the collected light (reflected or emitted), thecollection aperture must be imaged to the eye pupil assuming that theaperture has structure in the non-scanned direction. The pivot point ofthe collection scanning must be imaged to the eye pupil.

A solution that addresses these issues is to bring the scanner as nearas possible to the pupil splitting plane and have the images at bothlocations be conjugated to the iris. This would reduce or eliminatevignetting in color as well as fluorescent images.

Background Subtraction Scenarios

It is an aspect of the present invention to improve image quality/signalof BLFI systems or methods by minimizing or enabling easy removal ofmotion artifacts and background/stray-light signal using a step-scanillumination/detection scheme and refined algorithms. Here the imagepost processing is explained in the de-scanned detection scheme forcolor imaging.

The scanner steps to the first position. A red, a green and a blue imageor a color image will be acquired as fast as possible and then thescanner steps to the next position. This cycle will be repeated untilthe whole field of view (FOV) is detected. For every scan position andevery color, a typical image will be acquired similar to the image shownin FIG. 5 for the case of IR illumination. The fundus is located in themiddle of the image. On both sides there is a transition region. In thiszone the intensity will decrease from the illuminated level to thebackground level.

On both sides of the transition zone a dark strip image with the samewidth as the illuminated bright strip image can be acquired. It iseasier and also possible to only acquire a single side dark image. But,because of the dark image subtraction artifacts in vignetted systems,collecting dark images from both sides is preferred. The so detectedstripe or strip images will be registered to compensate for motionartifacts between the two adjacent stripe images. Because the timebetween two neighboring stripes of one color is only a few milliseconds,the motion displacement is only on the order of a few pixels. Therefore,the transition zones could be used to compensate the motiondisplacement. It is preferred to extend the width of the illuminationzone to have enough overlap without shading between the stripe images.

The so registered stripe images for one color can be merged together toone full FOV image. Because the image contains data from a much broaderzone than the illuminated scanner steps, the dark image parts willoverlap to the bright image parts of the next two stripes. The sooverlapped image can be dissected into a bright and two dark imageswithout interruptions and in a pixel correspondent way. The two darkimages will be averaged and then subtracted from the bright image. Theso processed image could show stripe like intensity variations. Tocompensate for them, a saturation adaption in the borders of the stripescan be performed.

An alternative solution would be to have a transition zone of at leasthalf the bright stripe width. Then the transition zones on both sides ofthe bright stripe could be also merged to a “transition image” withoutinterruptions and pixel correspondent to the bright and the dark images.The reconstructed image will then be calculated by adding the transitionimage and the bright image and subtracting both of the dark images takenon either side of the bright image. The basic idea behind this is thatin the border of an illuminated stripe because of optical aberrations,defocus in combination with an extended retina thickness, a certain partof the illumination brightness will be transferred to the transitionzones. So if the transition zones will be added to the bright image, allthe transferred intensity will be corrected so the reconstructed imagewill show much less stripe intensity artifacts.

The subtraction of a dark image could correct all parasite light effectslike scattering in the eye lens and auto fluorescence of the eye lens ifthey are not structured. But because the reflexes of the ophthalmic lens(OL) and scan lens (SL) are highly structured they will not be identicalin the bright and dark images and therefore a dark image subtractioncould cause additional artifacts in the final image. For this reason theOL and SL reflexes can be suppressed by the help of a “no eye image”.The no eye image will be acquired in the same way described above butwith a black cap in front of the ophthalmic lens so that the eye isblocked. The no eye images will be specific for every color and everyfocus position and could be acquired one time at the time of manufactureof the instrument or daily as part of an instrument initializationprotocol. The no-eye image would then be stored in a data base. It isalso possible but not preferred to acquire the no eyes images directlyin front or after each patient image.

Before the image reconstruction, the no eye image will be subtractedfrom the patient image. To do so the unregistered stripe images withbright, dark and transition zones will be subtracted by thecorrespondent no eyes stripe images.

In the bright image there are typically two smaller regions close to theOL front side reflex and in the near of the optical nerve head where theimage brightness is much higher than in the rest of the image. For thedark and no eye image subtractions, it is necessary that all images arenot saturated. If camera sensors with a small dynamic range will beused, the signal to noise ratio could then be limited in the rest of thereconstructed image. To get better image quality it is preferred torealize high dynamic range (HDR) stripe images in the nerve head- and OLreflex regions. All HDR-methods known from the state of the art could beused therefore.

For all fluorescence images, the SNR in the reconstructed image is themost important quality feature. In fluorescence applications, the darkimages contain no reflex light because of the wavelength shift betweenillumination and detection. So the dark images are mostly affected byauto fluorescence light of the eye lens and therefore the dark imageonly contains a small amount of structure. To get better SNR under thesecircumstances it is preferred to locally average the dark images toreduce the noise and to adapt the degree or range of averaging to thedegree of structure.

In the following section basic parameters for the optimization for thetransition zone between bright- and dark image will be explained. FIG. 7shows depth discrimination functions corresponding to the part of lightreflected in a plane at a certain distance to the focus (x-axis) thatcould be detected behind the confocal aperture stop. For light that willbe reflected in the focus region, the detection efficiency is 1 forevery measurement principle. The detection efficiency will decrease ifthe distance to the focus is increased and the exact functionality isdescribed by a specific depth discrimination function. All curves dependon the detection wavelength and the pupil size in the eye but could bequalitatively compared by the help of the diagram above.

The white curve 1201 in FIG. 7 shows the depth discrimination functionof a confocal scanning laser ophthalmoscope with a closed pinhole. Thedetection efficiency will decrease quadraticaly with the distance to thefocus. It has the strongest confocal suppression level for all focusdistances compared to the other detection methods.

If the pinhole will be opened (to around 10 airy) the curve will bechanged to the blue one 1202. It has the same functionality but isscaled by a factor of 10 in the x-direction.

A line scanning laser ophthalmoscope with single line detection is shownin the red curve 1203. The function is around the square root of thewhite curve. That means for all distances the confocal level is muchreduced.

The yellow curve 1204 shows a broad line scanner with a multi-lineillumination and detection (around 10 lines). With regard to thefunctionality it is a 10 times scaled version of the red curve in thex-direction. The confocality level is much less than for the otherfunctions. The green curve 105 is equivalent to the red one but with adark line subtraction. The dark line has a certain distance to thebright line that could be controlled. For small out of focus distancesthe dark line will be dark and the subtraction will have no effect.Therefore for small out of focus distances, the red and the green curvesare identical. Beginning with a certain distance to the focus the lineimage will be blurred so much that a part of the illumination brightnesswill illuminate the dark line too. Than a dark line subtraction affectsthe functionality of the curve as can be seen in a split of the greenand red curve. For larger defocuses the depth discrimination with darkimage subtraction is much stronger than for the line scanner withoutdark line subtraction.

The violet curve 1206 is a multi-line illumination and detectioncombined with a dark multi-line subtraction and shows the properties ofa specific BLFI variant with background subtraction. It is characterizedby a very small near out of focus suppression and a very strong far outof focus suppression compared to the other detection methods.

For an efficient detection of light back scattered by the retina or offluorescence light from the retina, it is important to have a very smallnear out of focus discrimination. Because the retina has a certainthickness and the image curvature could be different to the retinacurvature, a highly sensitive imaging of all light from the retina couldonly be realized with such a system of small near out of focusdiscrimination.

Scattering/fluorescence light from the eye lens or reflex light from thecornea have a much larger distance to the focus region marked by the redarrow 1207 in FIG. 7. To get a good contrast in the retinal images, itis important to strongly suppress these far out of focus signals. For anoptimal system for retinal diagnostics, a combination of weak near outof focus suppression with a very strong far out of focus suppression isrequired. A confocal scanning laser opthalmoscope can only influence thedepth discrimination function by opening the pinhole size. This willinfluence the near and far out of focus discrimination but not the ratioof both.

For BLFI it is possible to choose the number of pixel lines that will beilluminated and detected at one time and with it the near out of focussuppression. But with the distance between bright and dark images inpixel lines, it is possible to determine the point where the violetcurve and the yellow curve will split and with it the far out of focussuppression of the violet curve. This basic property of a BLFI with darkimage subtraction will give this very significant advantage of verysensitive and high contrast fundus imaging.

The distance between bright and dark images can be fixed to a typicalpatient as described by a population average or can be made variablewith the help of an appropriate detector with selective line read out.Thus this distance can individually be adapted to each patient andapplication e.g. by one or several images taken in advance of the imagefinally used for diagnostics. So an individually optimized image isgenerated.

While the considerations above are made in the context of a descanningsystem using a stepwise scanning of the illumination, the considerationscan also be applied to non-de-scanned systems and/or continuous scanningsystems

Pupil Splitting Considerations

Another aspect of the present invention is to improve imagequality/signal of BLFI systems or methods by further minimizing overlapbetween illumination and detection paths or reducing reflexes using adifferent pupil splitting arrangement than in the prior art. Thereflexes from most optical surfaces can be eliminated by minimizingoverlap between illumination and collection light at the opticalsurfaces. This is best accomplished by minimizing the etendue of theillumination and collection light in one dimension and then using pupilsplitting to separate their optical paths in this dimension. Pupilsplitting can be accomplished using a special arrangement of a splittingoptical element e.g. a mirror. The basic task of the splitting mirror isto combine/split the illumination- and the detection ray path of a broadline scanner in a way that the illuminating path does not overlap withthe detection path in regions of the eye which show highreflectivity-like the cornea surface or have strongscattering/fluorescence structures like the natural lens. This isoptimally achieved by a splitting mirror leading to pupil separation asshown in FIG. 8e . In this figure the green area 801 indicates area ofthe detection path and yellow areas 802 are those used by theillumination path. The black area indicates a zone (here referred to as“no-mans-zone”) which is not used by either the illumination or thedetection path and might actually be blocked by special apertures in theillumination respective of the detection paths. The optimal illuminationaccording to FIG. 8e is done at two caps of a circular disc, while thedetection is done centrally covering an ellipsoid or in a preferredcase, a circular(not shown) disc pattern, both being separated by a“no-mans-zone” with nearly rectangular outer shape. The design has beennamed “DOD” since the letters are representative to the splittingshapes. In addition this pupil separation pattern and the splittingoptical element which realizes that pupil separation is oriented withits longer edge of the rectangular “no-mans-zone” and thus orequivalently with the base of the caps describing the illuminationaperture parallel to the illumination slit generated at the retina.

It is important that in contrast to the embodiment disclosed in PCTPublication No. WO 2012/059236 which essentially resembles thearrangement illustrated in FIG. 8b , the illumination and the detectionareas are reversed. Thus in the prior art, the images generated by usingthe peripheral regions of the aperture are more affected by aberrationsof the cornea than the image of the slit, which is generated by theperipheral regions of the aperture in the disclosed invention. Second,the orientation of the “no-mans-zone” relative to the illuminated slitat the retina is not perpendicular as it is the case in the prior art.Thus the crossing of the detection path and the imaging path can bearranged to be outside the natural lens, minimizing the detection ofscattered light.

In additional contrast to prior art designs considered in Muller USPatent Publication No. 2010/0128221, the pupil splitting arrangementillustrated in FIG. 8e shows two caps or hemispheres of a disc asillumination aperture. The advantage of the hemispheric apertures isthat more light is used for illumination of the slit at the retina thanwith the ring or elipsoidial illuminations of the prior art. This isespecially important when LEDs, which are limited in their output powerare used for fluorescence applications. Further, prior art keeps silentrelated to a “no-mans-zone” and also to the orientation of theillumination aperture relative to the orientation of the illumination atthe retina.

In general for BLFI, other pupil separation areas can be envisioned asshown in FIGS. 8a, 8c , and 8 d.

In a further embodiment, the splitting optical element creating theillumination/detection aperture could be variable or exchangeable. Thisvariation or exchange will allow for adaptation of the aperture todifferent corneas of different persons e.g having to different cornealcurvatures or corneal aberrations or depending on the imaging modalityused. E.g. for fluorescence imaging the “no-mans zone” can be madethinner or an aperture separation omitted altogether to allow detectionof faint fluorescence light all over the aperture when a wavelengthsplitter or filter is used somewhere in the detection path.

Further descriptions of pupil splitting considerations will now beconsidered.

If the illumination and collection on the pupil/cornea are displaced inthe horizontal direction, we would need to minimize the etendue in thisdimension by illuminating a vertical line on the retina. Thisillumination could be either in the form of two bands on opposite sidesof the collection aperture or, for a smaller pupil, illumination on onlyone side as shown in FIG. 9.

Note that the pupil splitting and retina illumination could both berotated by 90 degrees if scanning vertically across the retina with ahorizontal line was desired.

In addition to reducing or eliminating overlap between the illuminationand collection at the optical surfaces, this approach also minimizes theoverlap within the eye, greatly reducing issues with unwanted light fromscattering or fluorescence. In the sections below we first analyze theoverlap of the light within the eye, then extend the approach toconsider the overlap of the light on optical surfaces of the imagingsystem outside of the eye.

Overlap between illumination and collection light within the eye

As shown in FIG. 10, the overlap between illumination and collectionwill extend over an axial distance from the retina toward the pupil ofof I L/(i+d), where:

-   d—Width of no-mans land (distance between illumination and    collection on pupil)-   i—width of illumination on retina-   L—length of eye

Minimizing overlap between illumination and collection in the eye isimportant for improving contrast as it reduces collection of unwantedscattered light from the eye. In addition, the regions of overlap andnon-overlap are imaged throughout the optical system, so by making surethat no optical surfaces are in axial positions conjugate to thisoverlap region, one can eliminate issues with reflexes from the system.

A complete optical diagram is shown in FIG. 11 to fully illustrate thepoint. The collection aperture and sensitive region on the cameratogether define the region between the green line where the light mustcome from to be detected. The illumination aperture and low etendue inthe pupil splitting direction ensure that illumination light does notintercept these regions at any of the optics. Note that in this diagram,the separation between illumination and collection has been exaggerated.Typically, the pupil size is only a few millimeters, and therefore theillumination and collection light will be roughly a millimeter apart onthe lenses.

One must also consider the issue of overlap between illumination andcollection for optical surfaces imaged behind the retina. FIG. 12 showsjust the critical rays from the top of the collection and bottom of theillumination shows that the region of overlap behind the retina extendsa distance of i L/(d−i):

Here red denotes the bottom of the illumination aperture and orangedenotes the top of the collection aperture. Note that this overlappingregion will be imaged into the space from the imaged retinal planebehind the ophthalmic lens toward the cornea. As reflexes from theophthalmic lens are of primary concern, the location of the ophthalmiclens relative to this imaged region is critical, and the ratio of i to dshould be selected appropriately to make sure this region is shortenough to avoid the ophthalmic lens.

The reason for the difference in overlap between in front of and behindthe retina is that the side of the lines where light is an issue flipsbetween in front of and behind the retina. Note that for all of theabove examples, the overlap between illumination and collection isnearly complete in the dimension perpendicular to the pupil splittingalong the line of illumination on the retina as shown in FIG. 13a . Alsonote that pupil splitting along the line of illumination leads tosignificant overlap as shown in FIG. 13 b.

So far, we have assumed that the “pupil splitting” aperture is imaged tothe pupil or cornea. However, for a de-scanned system, the splitting canbe at any image plane from the pupil toward the imaging system. Byplacing the pupil splitting at the cornea, we have optimized theseparation between illumination and collection at the cornea, at theexpense of good splitting at the ophthalmic lens. By placing the pupilsplitting roughly halfway between the cornea and ophthlamic lens, oneshould be able to have the beams nearly overlap at both the cornea andopthalmic lens thus reducing the region without overlap inside the eye,but extending the distance for which there is no overlap in front of theeye. Note that changing of the refractive error correction could impactthe location of the pupil splitting.

Ophthalmic Lens Tilting

Another goal of the invention is to improve image quality/signal of BLFIsystems by further minimizing reflexes such as those created by theophthalmic lens (OL). One was this can be accomplished is by using atiltable ophthalmic lens. For high myopic eyes the OL reflex will beconcentrated/focused to the centre of the image. Due to this even smallOL-reflectivities could result in very small and intensive reflexes. Insuch a situation it is nearly impossible to subtract the reflexeswithout any visible rest artifacts. The OL-reflex diameter is related tothe defocus of the eye. It is not necessary to remove the whole reflex.If it is defocused enough it could be subtracted by the reflexsubtraction.

The basic idea to suppress the OL reflex is to bring this reflextemporarily to other parts of the fundus image and to combine some ofthese images to a reflex free image. Because the most significant OLreflex is most critical if it is concentrated to a very small imageregion it is sufficient to shift it only a little bit with regard to theimage content. This could be done with the help of a changed fixationtarget the patient will be asked to gaze to. It could be also done byusing the motorized tilt and swivel functionality of the fundus camerato change the image contend behind the OL reflex. But most preferred itshould be done with the help of a motorized ophthalmic lens tilt.Automated tilting could be realized in a number of ways including butnot limited to: piezo elements, voice coil elements, cam shaftembodiments, linear solenoids, and galvanometers.

The basic imaging procedure is to take a normal image consisting ofstripes than tilt—preferably perpendicular to the orientation of theillumination line on the retina—the OL by a few degrees and image allstripes in the center of the image that where effected by the OLreflexes in the first image again. A combination of these images willgive a reflex free image. One could also acquire two partial images,which when combined could form the complete image. For instance, thefirst image could consist of the complete image minus the horizontalband containing the reflexes, and the second image could consist of thishorizontal band with the reflexes shifted to a different verticalposition.

The tilt angle will be determined in such a way that it will displacethe OL reflex to have no reflex overlap with the not tilted image. Inthe case of strong myopic eyes where the intermediate image is locatednear the OL back side, the tilting angle will be determined to reflectout the OL back side reflex from the detection aperture. So incombination with a reflex subtraction the OL lens tilt could suppressthe OL reflexes that no visible rest artifacts will remain.

Image Quality Considerations

For best imaging quality, we need to do several things:

-   -   1. Maximize optical efficiency by maximizing the illumination        and collection areas on the pupil    -   2. Eliminate reflexes from optics and the eye (color and IR        imaging) and scattering from the lens (all imaging)    -   3. Minimize focus/aberration issues by limiting collection        aperture to within a small (roughly 1.5 mm diameter) circle

As described in the pupil splitting design that maximizes opticalefficiency while minimizing reflexes and scattering is shown in FIG. 9.However, the collection aperture needs to be limited for severalreasons:

-   -   1. Optical aberrations of the eye    -   2. Increased depth of view to simplify focusing, particularly        for novice users. Note—this requirement may be addressed by an        autofocus function    -   3. Increased depth of view to address variations in the surface        of the retina relative to best focus, particularly for large        field of view imaging.    -   4. The optimum aperture in the absence of other constraints is        circular, with a diameter somewhere between that of a standard        non-myd fundus camera (diameter of 1.2 mm) and the FF-450. For        ultra-wide field imaging, s the aperture diameter may need to be        smaller to address the increased variation in best focus in the        periphery.

Ideally, the optimum diameter circle can fit within the collectionaperture area defined above. However, if it can't, then the collectionaperture should be the overlap between such a circle, the pupil, and therectangular aperture above. The resulting collection and illuminationapertures for a small and large pupil are illustrated in FIG. 14.

For instrument and operation simplicity, it is highly desirable toimplement a single pupil splitting design that works for all sizes ofpupils and for both fluorescence and color/IR imaging. Switching betweendifferent designs for different situations leads to the followingissues:

-   -   1. There is a relatively uniform distribution of pupil sizes        from small to large, and variations in pupil size during        acquisition, so it will often not be clear which is the optimum        setting to use    -   2. IR imaging is used for alignment during fluorescence imaging,        therefore creating a conflict if the designs for IR and        fluorescence imaging are different    -   3. The primary differences between small and large pupil designs        are:    -   4. For large pupils, illumination on both sides of the        collection aperture for increased optical efficiency    -   5. For small pupils, off-axis collection    -   6. The issue of off-axis collection is easily addressed as one        can move the collection aperture toward the center of the pupil        for larger pupils. The questions then become:    -   7. Is illumination on both sides of the collection aperture        necessary for maximizing signal in the large pupil design?    -   8. Is the illumination of the iris an issue if the large pupil        design is used for small pupils?    -   9. If all else is equal, the small pupil design is preferable        from a design perspective, as illumination from only one side of        the pupil simplifies the optical design, allowing an approach        with a fixed collection aperture as shown in FIG. 15.

If one uses this design, the illumination should probably come frombelow so as this avoids use of the upper part of the pupil in withlarger pupils, and this area is often covered by droopy eyelids in olderpeople.

In addition, we need to consider whether the pupil splitting should bedifferent for fluorescent imaging versus color/IR imaging as opticalefficiency is of greater concern for fluorescence imaging.

The unique features of fluorescence imaging relative to color/IR imagingare:

-   -   1. Reflexes can be blocked by a dichroic mirror, and therefore        aren't an issue, allowing more flexibility in the illumination        area    -   2. Fluorescence signal is generated at significantly lower        efficiency (roughly a factor of 10 for FA and 100 for FAF) than        scattering, reducing signal levels

The similarities between fluorescence imaging and color/IR imaging are:

-   -   1. The collection aperture limitations to maintain quality        focusing are roughly the same (there may be a slight difference        due to larger spectral widths for the color imaging)    -   2. The need to avoid overlap between illumination and collection        in the lens to maintain contrast is similar.

Assuming that it is possible to illuminate the entire pupil forfluorescence imaging as demonstrated with the BLFI, choosing toilluminate on only one side of the collection aperture will reduce theoptical efficiency by a factor of roughly 2 to 6, depending on pupilsize and whether off-axis collection is used.

Dynamic Illumination/Detection Width Adjustment

It is possible to eliminate the reflexes from the ophthalmic lens bylimiting the illumination width on the retina and the collection widthof the detection. This is not a viable option for the entire retinalimage as it would require collection and mosaicking of too many lines ofillumination, resulting in an overly long acquisition time.

However, the need for a reduced width retinal illumination is limited tothe region where the reflexes are a concern, i.e. the central portion ofthe retina/ophthalmic lens. Therefore, if we can vary the illuminationwidth during the scan, we should be able to eliminate the reflexes inthe center of the image while only slightly increasing the acquisitiontime. For instance, if we needed to reduce the slit width by a factor of3 over 1 tenth of the image, we would have to first order an acquisitiontime of 3*0.1+0.9=1.2, or a 20% increase in time. Note that this has noimpact on total amount of illumination on the eye, integration time forany specific region, or amount of signal acquired for any portion of theeye.

As the illumination brightness and acquisition time for each individualslice is unchanged, the overall brightness of the image at each slicewill remain the same. The illumination width could be defined in avariety of ways including but not limited to: passing light through aslit, reflecting light from a mirror with a finite width, varying theextent of the light source. The collection width can be determined in avariety of ways including but not limited to: passing light through aslit, reflecting light from a mirror with a finite width, and activearea of a detector. Either one or both of the illumination or collectionwidths could be varied dynamically.

Although various applications and embodiments that incorporate theteachings of the present invention have been shown and described indetail herein, those skilled in the art can readily devise other variedembodiments that still incorporate these teachings. While thedescription is focused largely on ophthalmic imaging, it is believedthat some of the inventive concepts could have broader imagingapplications.

The following references are hereby incorporated by reference:

PATENT LITERATURE

-   U.S. Pat. No. 3,547,512 Baer et al. “Optical apparatus providing    focal-plane specific-   U.S. Pat. No. 4,135,791 Govingnon et al. “Reduced glare scanner”-   U.S. Pat. No. 4,732,466 Humphrey “Fundus camera”-   U.S. Pat. No. 4,768,874 Webb et al. “Scanning optical apparatus and    method”-   U.S. Pat. No. 4,991,953 Webb et al. “Scanning laser vitreous camera”-   U.S. Pat. No. 5,028,802 Webb et al. “Imaging apparatus and methods    utilizing scannable microlaser source”-   U.S. Pat. No. 5,177,511 Feuerstein et al. “Apparatus for producing    images of an object and in particular for observing the rear    portions of the eye”-   US Patent Publication No. 2010/0128221 Muller et al. “Laser scanning    digital camera with pupil periphery illumination and potential for    multiply scattered light imaging”-   US Patent Publication No. 2009/0244482 Elsner et al. “Laser scanning    digital camera with simplified optics and potential for multiply    scattered light imaging”-   US Patent Publication No. 2004/0207811 Elsner “Device for digital    retinal imaging”-   PCT Publication No. WO 2012/059236 Bublitz et al. “Fundus camera    with strip-shaped pupil division, and method for recording    artifact-free, high resolution fundus images”-   US Patent Publication No. 2007/0291277 Everett et al. “Spectral    domain optical coherence tomography system”-   US Patent Publication No. 2012/0249956 Iyer et al. “Systems and    methods for efficiently obtaining measurements of the human eye    using tracking”-   US Patent Publication No. 2006/0228011 Everett et al. “Method and    apparatus for measuring motion of a subject using a series of    partial images from an imaging system”-   German Patent Application No. DE 10 2011 053 880.1

NON-PATENT LITERATURE

-   Poher et al. “Improved sectioning in a slit scanning confocal    microscope” Optics Letters 33(16), 1813-1815 2008.

What is claimed:
 1. A system for imaging the eye of a patient, saidsystem comprising: a light source for producing a beam of radiation;optics for directing the beam of radiation to the retina of the eye of apatient to illuminate a two-dimensional region on the retina; a detectorfor collecting light returning from the eye and generating outputsignals in response thereto; pupil splitting optics for separating thelight illuminating the retina from light returning from the retina,wherein the pupil splitting optics establish two regions of illuminationoutside of one region of detection and wherein the regions ofillumination and the region of detection are separated by a regionthrough which no radiation passes, and wherein the pupil splittingoptics can be adjusted so that either only one or both of theillumination regions are used during imaging; and means for moving thebeam to various locations across the retina of the eye such that aseries of two dimensional regions of the eye are illuminated.
 2. Asystem as recited in claim 1, wherein the pupil splitting isaccomplished in a first direction selected such that the etendue of theillumination beam is lower in the first direction of the pupil splittingthan in the orthogonal direction.
 3. A system as recited in claim 2,wherein the extent of the illumination in the pupil of the eye isnarrower in the lower etendue direction.
 4. A system as recited in claim3, wherein the angular distribution of the illumination light in thepupil is lower in the lower etendue direction than in the orthogonaldirection.
 5. A system as recited in claim 2, wherein the angulardistribution of the illumination light in the pupil in the lower etenduedirection is lower than in the orthogonal direction.
 6. A system asrecited in claim 2, wherein the beam illuminates an area on the retinawith a two-dimensional extent having a long axis and a short axis, andthe splitting direction leads to a no-man's zone near the cornea whichis oriented parallel to the long axis of the illuminated area on theretina.
 7. A system as recited in claim 1, wherein the means for movingthe beam is a scanner.
 8. A system as recited in claim 1, wherein themeans for moving the beam is a moving slit in front of the light source.9. A system as recited in claim 1, wherein the means for moving the beamis a transverse movement of the light source.
 10. A system as recited inclaim 1, wherein optics direct returning light to different regions onthe detector depending on the area of the retina being illuminated. 11.A system as recited in claim 1, wherein optics direct returning light tothe same region or regions on the detector regardless of the locationson the retina being illuminated.
 12. A system as recited in claim 1,further comprising: generating an image from the collected light,wherein the transverse extent of the illumination is visible in theimage; using the sharpness of the line between the illuminated andunilluminated areas to optimize the focus of the imaging system.
 13. Asystem as recited in claim 1, wherein the light returning from the eyecontains light reflected or emitted from other areas of the eye notilluminated by the source, and the system further comprises a processorfor subtracting the detector signals corresponding to the other areasfrom the signals corresponding to the imaged region and for generatingan image based on the subtraction.
 14. A system as recited in claim 13,wherein the optics for directing reflected or emitted light towards thedetector direct the light to the same region or regions on the detectorregardless of the locations on the retina being illuminated.
 15. Asystem as recited in claim 14, wherein the reflected light fromunilluminated areas is collected at locations above and below the regionon the detector where the reflected or emitted light from illuminatedareas of the retina.
 16. A system as recited in claim 1, wherein onlyone illumination region of the pupil splitting optics used when thepupil of the eye is small.
 17. A system as recited in claim 1, whereinthe illumination regions are separated vertically and only the lowerillumination region is used during imaging.
 18. A system as recited inclaim 1, wherein the light source comprises one or more LEDs and a laserand wherein the LEDs and laser are used for different imagingmodalities.
 19. A system as recited in claim 1, further comprising anoptical element for scattering the beam of radiation so that the beam ofradiation is enlarged at the pupil plane of the system.
 20. A system asrecited in claim 19, wherein the optical element is rotated duringimaging.